Compulsive cocaine (COC) abuse in humans is associated with an intermediate withdrawal phase (3.10 days after withdrawal), which may be associated with a high rate of recidivism. This proposal is to continue and expand our examinations of the residual effects of chronic COC pretreatment on the DA regulatory mechanisms. Results from these examinations are expected to facilitate the development of effective pharmacotherapeutic modes for repeated COC abuse. It is hypothesized that the time-dependent changes in dopamine (DA) soma/dendritic autoreceptors form an useful model of the COC withdrawal phases in humans. Moreover, alterations in non-autoreceptor regulation of DA neurons might be responsible for initiating the gradual development of the autoreceptor supersensitivity and, as such, may provide for an early intervention that may block the development of the autoreceptor supersensitivity. Animals will be pretreated with continuous COC (40 mg/kg/day, s.c.) for 14 days; intermittent injection group receiving the equivalent daily dose will be included for direct comparison and contrast. First, we will complete the determination of the time-dependent autoreceptor sensitivity changes in the identified nigrostriatal (N-ST) and mesoaccumbens (M-ACC) DA neurons. In vivo, this will be accomplished by microiontophoretic application of DA or quinpirole (selective D2 agonist), and also by determining the number of spontaneously active DA neurons by population sampling. In vitro sensitivity of DA neurons to bath-applied DA or quinpirole will be measured by inhibition of spontaneous firing rates (extracellular recording) or by membrane hyperpolarization and/or fall in the membrane resistance (intracellular recording). Our intracellular recording technique allows identification of the projection sites of recorded neurons by a double-labelling technique, thus allowing differential effects of chronic COC pretreatment to be examined in vitro. Possible changes in the indirect modulation of DA neurons by substantia nigra/VTA D1 and 5-HT1B receptors will be determined following continuous COC pretreatment. The enabling effect of SKF 38393 selective D1 agonist on quinpirole subsensitivity on day 1 of COC withdrawal will be established in vivo complemented by in vitro studies measuring changes in the modulatory effects of SKF 38393 and CGS 12066B (a selective 5-HT1B agonist) on the GABA-B-mediated postsynaptic potentials in DA neurons. Finally, early intervention with bormocriptine (selective D2 agonist), SCH 23390 (selective D1 antagonist), and fluoxetine (5-HT reuptake blocker) will be evaluated for the ability to inhibit the development of the day 7 autoreceptor supersensitivity, thus providing results parallel to the documented or hypothesized efficacy of these agents in maintaining COC abstinence in humans.